6 alpha-Fluoro-16 alpha-methyl-21-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1967

Report date:

1967

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not applicable

Principles of method if other than guideline:

The study was conducted prior to implementation of the OECD test guidelines.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fluocortolone

EC Number:

205-811-5

EC Name:

Fluocortolone

Cas Number:

152-97-6

Molecular formula:

C22H29FO4

IUPAC Name:

6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione

Details on test material:

- Name of test material (as cited in study report): 6-alpha-fluoro-16-alpha-methyl-delta-1,4-pregnadiene-11ß, 21-diol-3, 20-dione (ZK10445)
- Lot/batch No.: 1008

Test animals

Species:

rat

Strain:

other: Caesarean-derived weanling albino rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: males: 93-95 g for the preliminary study and 157 g-208 g for the dose range finder, females: 88-91g for the preliminary study and 151 - 207 g for the dose range finder
- Housing: Individually
- Diet (e.g. ad libitum): Purina Laboratory Chow (meal) ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: 8 d


ENVIRONMENTAL CONDITIONS
The rats were individually housed in temperature-controlled quarters.

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

A basal diet was fed to all animals for the eight-day acclimation period. The drugs were then incorporated into the diet by means of a mechanical mixer to yield concentrations
required to provide the desired daily intake of compound.

Vehicle:

not specified

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

A. preliminary study: 10 days exposure plus 18 days post exposure time (resulting in 4 weeks test)
B. range finding study: 15 days

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.3 mg/kg bw/day (nominal)

Remarks:

dose range finder

Doses / concentrations 2

Dose / conc.:

1 mg/kg bw/day (nominal)

Remarks:

dose range finder

Doses / concentrations 3

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

dose range finder

Doses / concentrations 4

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

Preliminary study

Doses / concentrations 5

Dose / conc.:

9 mg/kg bw/day (nominal)

Remarks:

Preliminary study

Doses / concentrations 6

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

Preliminary study

No. of animals per sex per dose:

A. preliminary study: 30/sex/dose
B. range finding study: 2/sex/dose

Control animals:

yes, concurrent vehicle

other: preliminary study: 9 mg/kg prednisolone as positive control.

Results and discussion

Effect levels

Key result

Dose descriptor:

LOAEL

Effect level:

>= 0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: BW gain

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

A. preliminary study: 15 animals receiving fluocortolone died in second week on treatment (13 rats of high dose group, 2 rats in mid dose group). Despite the cessation of test substance on 11th day further 16 animals (12 rats of high dose group, 3 rats of mid dose group, 1 rat of low dose group) died until end of study after 4 weeks. Decrease of body weight in week 1. Reduced bw gain until end of study. Reduced food consumption.

B. range finding study: All animals survived study period. Reduced bw gain in low dose group. Bw loss in mid and high dose groups.

Applicant's summary and conclusion

Conclusions:

In a preliminary 4 weeks study rats (30/sex/dose) were treated orally with 3, 9 or 50 mg/kg fluocortolone for 10 days and suviving animals were observed until end of study. 15 rats died during treatment period, additional 16 animals died in post exposure period. Animals showed decreased body weight and food consumption in week 1 and reduction of bw gain until end of study.

In a second range finding study rats (2/sex/dose) were treated orally with fluocortolone (0.3, 1.0, 3.0 mg/kg). All animals survived study period. Reduced bw gain in low dose group and bw loss in mid and high dose groups was observed.

The low adverse effect level was determined at the lowest dose level of 0.3 mg/kg.

Executive summary:

In a subchronic toxicity study (similar to OECD test guideline 407 but conducted prior to implementation of the test guidelines, Fluocortolon was administered to 30 albino white rats/sex/dose for the preliminary study and 2 albino white rats/sex/dose for the range finder study in diet, at dose levels of 0, 3, 9, and 50 mg/kg bw/day (preliminary study) and 0, 0.3, 1, and 3 mg/kg bw/day (range finder study).

In the preliminary 4 weeks study rats (30/sex/dose) were treated orally with 3, 9 or 50 mg/kg fluocortolone for 10 days and surviving animals were observed until end of study. 15 rats died during treatment period, additional 16 animals died in post exposure period. Animals showed decreased body weight and food consumption in week 1 and reduction of bw gain until end of study. In the range finder study rats were treated with 0.3, 1, and 3 mg/kg bw/day. The animals showed a decreased body weight gain from 1.0 mg/kg bw/day and at 3.0 mg/kg bw/day. An increased body weight gain was only observed at 0.3 mg/kg bw/day. Thus, based on these results the LOAEL is > 0.3 mg/kg bw/day.